KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi 590010, Karnataka, India.
Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi 590010, Karnataka, India.
ACS Biomater Sci Eng. 2020 Sep 14;6(9):4969-4984. doi: 10.1021/acsbiomaterials.0c00429. Epub 2020 Aug 21.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The destructive nature of the disease makes it difficult for clinicians to manage the condition. Hence, there is an urgent need to find new alternatives for HCC, as the role of conventional cytotoxic drugs has reached a plateau to control HCC associated mortality. Antioxidant compounds of plant origin with potential anti-tumor effect have been recognized as alternate modes in cancer treatment and chemoprevention. Resveratrol (RS) is a model natural nonflavonoid drug known for its anti-cancer activity. However, its clinical application is limited due to its poor bioavailability. The current research work aims to formulate, optimize, and characterize RS loaded cationic liposomes (RLs) for specific delivery in HCC. The optimized liposomes formulation (RL5) was spherical with a vesicle size (VS) of 145.78 ± 9.9 nm, ζ potential (ZP) of 38.03 ± 9.12 mV, and encapsulation efficiency (EE) of 78.14 ± 8.04%. cytotoxicity studies in HepG2 cells demonstrated an improved anti-cancer activity of RL5 in comparison with free RS. These outcomes were supported by a cell uptake study in HepG2 cells, in which RL5 exhibited a higher uptake than free RS. Furthermore, confocal images of HepG2 cells after 3 and 5 h of incubation showed higher internalization of coumarin 6 (C6) loaded liposomes (CL) as compared to those of the free C6. Pharmacokinetic and pharmacodynamic (prophylactic and therapeutic treatment modalities) studies were performed in -nitrosodiethylamine (NDEA-carcinogen) induced HCC in rats. Pharmacokinetic evaluation of RL5 demonstrated increased localization of RS in cancerous liver tissues by 3.2- and 2.2-fold increase in AUC and Cmax, respectively, when compared to those of the free RS group. A pharmacodynamic investigation revealed a significant reduction in hepatocyte nodules in RL5 treated animals when compared to those of free RS. Further, on treatment with RL5, HCC-bearing rats showed a significant decrease in the liver marker enzymes (alanine transaminase, alkaline phosphatase, aspartate transaminase, total bilirubin levels, γ-glutamyl transpeptidase, and α-fetoprotein), in comparison with that of the disease control group. Our findings were supported by histopathological analysis, and we were first to demonstrate that NDEA induced detrimental effect on rat livers was successfully reversed with the treatment of RL5 formulation. These results implied that delivery of RS loaded cationic liposomes substantially controlled the severity of HCC and that they can be considered as a promising nanocarrier in the management of HCC.
肝细胞癌 (HCC) 是全球癌症相关死亡的主要原因之一。该疾病的破坏性使得临床医生难以控制病情。因此，迫切需要寻找 HCC 的新替代方法，因为传统细胞毒性药物在控制 HCC 相关死亡率方面已达到瓶颈。具有潜在抗肿瘤作用的植物源抗氧化化合物已被认为是癌症治疗和化学预防的替代模式。白藜芦醇 (RS) 是一种具有抗癌活性的典型天然非黄酮类药物。然而，由于其生物利用度差，其临床应用受到限制。目前的研究工作旨在制备、优化和表征 RS 负载阳离子脂质体 (RL)，以实现 HCC 的特异性递药。优化的脂质体配方 (RL5) 呈球形，具有 145.78 ± 9.9nm 的囊泡大小 (VS)、38.03 ± 9.12mV 的 ζ 电位 (ZP) 和 78.14 ± 8.04%的包封效率 (EE)。在 HepG2 细胞中的细胞毒性研究表明，RL5 与游离 RS 相比具有更好的抗癌活性。HepG2 细胞摄取研究支持了这一结果，其中 RL5 的摄取量高于游离 RS。此外，在孵育 3 和 5 小时后，用香豆素 6(C6) 负载脂质体 (CL) 处理的 HepG2 细胞的共焦图像显示，与游离 C6 相比，其内化更高。在 -亚硝二乙胺 (NDEA-致癌物) 诱导的大鼠 HCC 中进行了药代动力学和药效学 (预防和治疗治疗方式) 研究。RL5 的药代动力学评价表明，与游离 RS 组相比，RS 在癌变肝组织中的定位分别通过 AUC 和 Cmax 增加 3.2 倍和 2.2 倍。药效学研究表明，与游离 RS 相比，RL5 处理的动物肝组织中的肝细胞结节明显减少。此外，在用 RL5 治疗后，HCC 荷瘤大鼠的肝标志物酶 (丙氨酸转氨酶、碱性磷酸酶、天冬氨酸转氨酶、总胆红素水平、γ-谷氨酰转肽酶和甲胎蛋白) 显著降低，与疾病对照组相比。我们的研究结果得到了组织病理学分析的支持，我们首次证明，NDEA 对大鼠肝脏的有害影响可以通过 RL5 制剂的治疗得到成功逆转。这些结果表明，RS 负载阳离子脂质体的递药可显著控制 HCC 的严重程度，可考虑将其作为 HCC 管理的有前途的纳米载体。
